EP0835265B1 - Inhibiteurs de l'agregation plaquettaire contenant des residus aminoacides aminergiques a chaines laterales a terminaison c - Google Patents

Inhibiteurs de l'agregation plaquettaire contenant des residus aminoacides aminergiques a chaines laterales a terminaison c Download PDF

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EP0835265B1
EP0835265B1 EP96909731A EP96909731A EP0835265B1 EP 0835265 B1 EP0835265 B1 EP 0835265B1 EP 96909731 A EP96909731 A EP 96909731A EP 96909731 A EP96909731 A EP 96909731A EP 0835265 B1 EP0835265 B1 EP 0835265B1
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Prior art keywords
group
compounds
platelet aggregation
amino
alkyl
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EP96909731A
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German (de)
English (en)
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EP0835265A1 (fr
Inventor
Norman A. Abood
Philippe R. Bovy
Daniel L. Flynn
Joseph G. Rico
Thomas E. Rogers
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GD Searle LLC
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GD Searle LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/75—Fibrinogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to pharmaceutical agents (compounds) which inhibit platelet aggregation in mammals.
  • Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism.
  • Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gp IIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
  • fibronectin Another large glycoprotein named fibronectin, possesses cell-attachment properties.
  • Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. See US Patents 4,517,686; 4,589,881; and 4,661,111.
  • Certain relatively short peptide fragments from the same molecule were found to promote cell attachment when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. See U.S. Patents 4,578,079 and 4,614,517.
  • U.S. Patent 4,683,291 inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets.
  • U.S. Patent 4,857,508 discloses tetrapeptides having utility as inhibitors of platelet aggregation.
  • European Patent Application 445,796 discloses acetic acid derivatives which have inhibitory action on the bonding of adhesive proteins to blood platelets as well as on blood platelet aggregation and cell-cell adhesion.
  • US 5,273,982 discloses acetic acid derivatives useful for inhibiting the binding of adhesive proteins to blood platelets and for inhibiting platelet aggregation.
  • European Patent Application 372,486 discloses N-acyl beta amino acid derivatives and their salts. Said compounds are useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis, and for inhibiting metastasis.
  • European Patent Application 381,033 discloses amidino or guanidinoaryl substituted alkanoic acid derivatives useful for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and tumors.
  • the present invention relates to a class of compounds represented by the formula: or a pharmaceutically acceptable salt thereof, wherein A is -CH- or -N-, and B is -CH- or -N-, with the proviso that when A is -N-, B is -CH-, and when B is - N-, then A is -CH-; -D-E- is -CH 2 -CH 2 - or with the proviso that when A is -N- then -D-E- is -CH 2 -CH 2 - and when B is -N- then -D-E- is R 1 and R 2 are independently selected from the group consisting of H, lower alkyl, and optionally substituted aralkyl; X is selected from the group consisting of -O- and -NH-; W is selected from the group consisting of R 5 is selected from the group consisting of H, lower alkyl, optionally substituted aralkyl, alkoxycarbonyl, acyl and
  • Such compounds and compositions have usefulness as modulators and/or inhibitors of platelet aggregation.
  • the invention also relates to the use of such compounds for preparing a medicament for therapeutically inhibiting or modulating platelet aggregation in a mammal in need of such treatment.
  • the present invention relates to a class of compounds represented by the formula I, described above.
  • a preferred embodiment of the present invention is compounds wherein W is W 2 .
  • lower alkyl refers to a straight chain or branched chain hydrocarbon radical having from 1 to 6 carbon atoms.
  • alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
  • aralkyl refers to a lower alkyl as defined above substituted by an aryl group, wherein the aryl group is an aromatic ring system composed of one or more aromatic or heteroaromatic rings such as phenyl, pyridyl, naphthyl, pyrimidinyl, biphenyl and the like.
  • Optionally substituted aralkyl refers to such a radical substituted by groups such as alkyl, alkoxy, hydroxy, halo, amino, nitro, cyano, carboxyl and the like.
  • acyl refers to a radical of the formula wherein R 10 is lower alkyl, aralkyl or aryl as defined above.
  • sulfonyl refers to a radical of the formula wherein R 11 is an alkyl or aryl group as defined above.
  • alkoxycarbonyl refers to a radical of the formula wherein R 12 is alkyl or aralkyl as defined above.
  • the compounds as shown in formula I can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
  • a bond drawn across a bond of a ring can be to any available atom on the ring.
  • pharmaceutically acceptable salt refers to a salt prepared by contacting a compound of formula (I) with an acid whose anion is generally considered suitable for human consumption.
  • pharmacologically acceptable salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, and tartrate salts. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Pharm. Sci., 66(1), 1-19 (1977) for additional examples of pharmaceutically acceptable salts.)
  • This invention also relates to the use of such compounds for preparing a medicament for inhibiting platelet aggregation and more specifically, to such a use involving the administration of compounds of Formula I to achieve such inhibition.
  • Compounds of the present invention bind to the group IIb/IIIa receptor disrupting the platelet/fibrinogen interaction necessary for thrombus formation.
  • the compounds modulate cell adhesion by competing with RGD containing ligands and by binding to RGD-directed receptors on cell surfaces.
  • compounds of the present invention may be administered orally, parenterally, or by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitonally.
  • the compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art.
  • the invention provides a class of novel pharmaceutical compositions comprising one or more compounds of the present invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier” materials) and if desired other active ingredients.
  • carrier non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants
  • the dosage regimen for treating a condition with the compounds and/or compositions of this invention is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 150 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. These may contain, for example, an amount of active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg.
  • a suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • a suitable daily dose would typically be about 0.01 to 50 mg/kg body weight injected per day in multiple doses depending on the condition being treated.
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the pharmaceutical compositions may be made up in a solid form such as granules, powders or suppositories or in a liquid form such as solutions, suspensions or emulsions.
  • the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
  • Scheme A, B1, B2 and 1-A are 1) general synthetic methods useful for preparing nonproteinaceous aminergic amino acids which form the W side chains of the compounds of the present invention, 2) synthetic methods useful for preparing intermediate alcohols and aldehydes for synthesis of the aminergic amino acids, 3) synthetic methods for preparation of pyrimidinyl and pyridinyl side chains and a 4) general synthesis of compounds of the formula I.
  • Scheme A illustrates the preparation of intermediate non-proteinaceous amino acid esters or amides 5 using as the key reaction a reductive amination between aldehydes 2 and secondary amines or amides 3 .
  • R 8 is selected from benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC), or allyloxycarbonyl (Alloc).
  • Compound 2 subsequently undergoes reductive amination with secondary amine 3, taken from NR 5 (R 6 ) wherein R 5 and R 6 are restricted to alkyl or optionally substituted aralkyl, pyrrolidine, piperidine, mono-substituted piperazines, or morpholine, to give N-protected amino acid esters 4 .
  • Reductive amination is effected using sodium cyanoborohydride, borane/pyridine complex, or sodium triacetoxy borohydride.
  • W 1 , W 2 containing amino acids are widely known and utilized.
  • Scheme B-1 illustrates the preparation of 5-(5-amidinylpyrimidin-2-yl)pentanoic acid 53a .
  • Pinner amidination of commercially available nitrile 46 affords amidine 47 , which is condensed with 2-cyano-3-dimethylaminoacrolein 50 (C. Reichart et al, Angew. Chem. Inter. Ed., (1972), 11 , 62) under basic conditions, preferably pyridine ⁇ triethylamine, at temperatures ranging from 20°C to reflux temperatures to afford the 5-cyanopyrimidine ester 51 .
  • Dilute aqueous acid hydrolysis of 51 gives nitrile 52 .
  • Ammonolysis in an alcoholic solvent, followed by treatment with HCl affords 5-(5-amidinylpyrimidin-2-yl)pentanoic acid 53a as the hydrochloride salt.
  • Scheme B-2 illustrates the preparation of 4-(6-aminoiminomethyl pyridin-3-yl)amino-1,4-dioxobutanoic acid HCl 53b .
  • 3-Amino-6-cyano-pyridine 54 was added to succinic anhydride 55 in an etheral solvent, preferably tetrahydrofuran (THF) at ambient temperature, to afford nitrile 56 .
  • etheral solvent preferably tetrahydrofuran (THF) at ambient temperature
  • THF tetrahydrofuran
  • Treatment of 56 with ammonia saturated in an alcoholic solvent, preferably methanol at 80°C for 24 hours gave 53b , isolated as the hydrochloride salt after treatment of the residue with HCl/dioxane.
  • Scheme 1A illustrates the general route utilized to obtain compounds of formula I.
  • a tertiary amine base N-methylmorpholine, N-methylpiperazine, triethylamine, di-isopropylethylamine
  • Example 1 The synthesis of Example 1 is illustrated in Scheme 1B.
  • Commercially available 57a and 58a were coupled, utilizing the standard iso-butylchloroformate/N-methylmorpholine procedure, to afford dipeptide 59a .
  • Hydrogenolysis of the CBZ protecting group (hydrogen atmosphere, palladium/C catalysis) gave the N-terminal amino dipeptide 60a .
  • Coupling of 60a with acid 53c J.G. Rico et al, J. Org. Chem . (1993) 58 , 7948
  • iso-butylchloroformate/N-methylmorpholine gave 61a, which afforded Example 1 after treatment with trifluoroacetic acid.
  • N-Cbz-Asp ⁇ -t-butyl ester (1.50 g, 4.46 mmol) and N-methylmorpholine (467 mg, 4.64 mmol) in 45 mL of CH 2 Cl 2 was added isobutylchloroformate (633 mg, 4.64 mmol). After stirring at -10°C for 10 minutes, N ⁇ -Boc-Lys t-butyl ester hydrochloride (1.57 g, 4.64 mmol) and N-methylmorpholine (467 mg, 4.64 mmol) were added sequentially. The reaction mixture was allowed to warm to room temperature while stirring for 18 hours.
  • Step B Preparation of H 2 N-Asp (Ot-Bu)-Lys (N ⁇ -Boc)Ot-Bu (4)
  • Step C Preparation of N-[4-[[4 (aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]-L-aspartyl]-L-lysine bistrifluoroacetate (Compound A)
  • the platelet-binding inhibitor activity of the compounds of the present invention can be demonstrated by the assays presented below.
  • PPP Platelet poor plasma
  • 400 il of the PRP preparation and 50 il of the compound to be tested or saline were preincubated for 1 minute at 37°C in a BioData aggregometer (BioData, Horsham, PA). 50 il of adenosine 5'-diphosphate (ADP) (50 im final concentration) was added to the cuvettes and the aggregation was monitored for 1 minute. All compounds are tested in duplicate.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Claims (6)

  1. Comoosé de formule:
    Figure 00320001
    ou un de ses sels pharmaceutiquement acceptables, dans laquelle :
    A est -CH- ou -N- et B est -CH- ou -N-, sous réserve que, quand A est -N-, B est -CH- et quand B est -N-, alors A est -CH-; -D-E- est -CH2-CH2 ou
    Figure 00320002
    sous réserve que, quand A est -N-, alors -D-E- est -CH2-CH2 et quand B est -N-, alors -D-E- est
    Figure 00320003
    R1 et R2 sont choisis, de façon indépendante, dans le groupe constitué par H, les groupes alkyle inférieurs et les groupes arylalkyle éventuellement substitués, les substituants facultatifs pouvant être choisis parmi alkyle, alcoxy, hydroxy, halogéno, amino, nitro, cyano, carboxyle ;
    X est choisi dans le groupe constitué par -O- et -NH-;
    W est choisi dans le groupe constitué par
    Figure 00320004
    R5 est choisi dans le groupe constitué par H, les groupes alkyle inférieurs, les groupes arylalkyle éventuellement substitués, les substituants facultatifs pouvant être choisis parmi alkyle, alcoxy, hydroxy, halogéno, amino, nitro, cyano, carboxyle ; les groupes alcoxycarbonyle, acyle et sulfonyle ;
    R6 est choisi dans le groupe constitué par H, les groupes alkyle inférieurs et les groupes arylalkyle éventuellement substitués, les substituants facultatifs pouvant être choisis parmi alkyle, alcoxy, hydroxy, halogéno, amino, nitro, cyano, carboxyle ;
    m est un entier choisi dans le groupe constitué par 3, 4 et 5 ;
    n est un entier choisi dans le groupe constitué par 2 et 3 ;
    p est un entier choisi dans le groupe constitué par 1, 2 et 3 ;
    r est un entier choisi dans le groupe constitué par 1, 2 et 3 ; et
    q est un entier choisi dans le groupe constitué par 0 et 1.
  2. Composé selon la revendication 1, dans lequel W est -(CH2)mN(R5)R6.
  3. Composé selon la revendication 2, qui est le bistrifluoroacétate de N-[4-[[4-(aminoiminométhyl)phényl]amino]-1,4-dioxobutyl]-L-aspartyl]-L-lysine.
  4. Composé selon la revendication 1, où W est W1.
  5. Composition thérapeutique comprenant une quantité thérapeutiquement efficace d'un composé selon l'une quelconque des revendications 1, 2, 3 ou 4 et un support pharmaceutiquement acceptable.
  6. Utilisation d'un composé selon l'une quelconque des revendications 1, 2, 3 ou 4 pour la préparation d'un médicament pour le traitement d'un mammifère dans le but d'inhiber l'agrégation plaquettaire.
EP96909731A 1995-04-11 1996-03-22 Inhibiteurs de l'agregation plaquettaire contenant des residus aminoacides aminergiques a chaines laterales a terminaison c Expired - Lifetime EP0835265B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02002913A EP1215215A1 (fr) 1995-04-11 1996-03-22 Inhibiteurs de l'agrégation plaquétaire contenant des résidues aminoacides ayant des chaínes latérales aminergiques à la terminaison C

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/419,793 US5811398A (en) 1995-04-11 1995-04-11 Platelet aggregation inhibitors containing C-terminal aminergic side chain amino acid residues
US419793 1995-04-11
PCT/US1996/003624 WO1996032415A1 (fr) 1995-04-11 1996-03-22 Inhibiteurs de l'agregation plaquettaire contenant des residus aminoacides aminergiques a chaines laterales a terminaison c

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EP02002913A Division EP1215215A1 (fr) 1995-04-11 1996-03-22 Inhibiteurs de l'agrégation plaquétaire contenant des résidues aminoacides ayant des chaínes latérales aminergiques à la terminaison C

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EP0835265A1 EP0835265A1 (fr) 1998-04-15
EP0835265B1 true EP0835265B1 (fr) 2002-08-07

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EP96909731A Expired - Lifetime EP0835265B1 (fr) 1995-04-11 1996-03-22 Inhibiteurs de l'agregation plaquettaire contenant des residus aminoacides aminergiques a chaines laterales a terminaison c

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US (1) US5811398A (fr)
EP (2) EP1215215A1 (fr)
JP (1) JPH11503450A (fr)
KR (1) KR19980703769A (fr)
AT (1) ATE221897T1 (fr)
AU (1) AU696893B2 (fr)
BR (1) BR9604914A (fr)
CA (1) CA2216996A1 (fr)
CZ (1) CZ291646B6 (fr)
DE (1) DE69622868T2 (fr)
DK (1) DK0835265T3 (fr)
ES (1) ES2181879T3 (fr)
NO (1) NO974537L (fr)
NZ (1) NZ305182A (fr)
PT (1) PT835265E (fr)
WO (1) WO1996032415A1 (fr)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5039805A (en) * 1988-12-08 1991-08-13 Hoffmann-La Roche Inc. Novel benzoic and phenylacetic acid derivatives
US5256812A (en) * 1989-01-31 1993-10-26 Hoffmann-La Roche Inc. Carboxamides and sulfonamides
CA2008116C (fr) * 1989-02-23 2001-11-20 Thomas Weller Derives de glycine
CA2037153A1 (fr) * 1990-03-09 1991-09-10 Leo Alig Derives de l'acide acetique
US5273982A (en) * 1990-03-09 1993-12-28 Hoffmann-La Roche Inc. Acetic acid derivatives
US5481021A (en) * 1991-03-06 1996-01-02 G. D. Searle & Co. Phenyl amidines derivatives useful as platelet aggregation inhibitors
US5220050A (en) * 1991-05-17 1993-06-15 G. D. Searle & Co. Peptide mimetic compounds useful as platelet aggregation inhibitors
HUT63609A (en) * 1992-03-10 1993-09-28 Sandoz Ag Process for producing new derivatives and isosters of beta-amino acids and pharmaceutical compositions comprising such compounds

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JPH11503450A (ja) 1999-03-26
NO974537D0 (no) 1997-10-01
AU5331696A (en) 1996-10-30
DE69622868D1 (de) 2002-09-12
ES2181879T3 (es) 2003-03-01
NZ305182A (en) 1998-07-28
DK0835265T3 (da) 2002-10-28
DE69622868T2 (de) 2003-04-10
KR19980703769A (ko) 1998-12-05
PT835265E (pt) 2002-11-29
EP1215215A1 (fr) 2002-06-19
US5811398A (en) 1998-09-22
ATE221897T1 (de) 2002-08-15
BR9604914A (pt) 1998-07-21
AU696893B2 (en) 1998-09-24
CA2216996A1 (fr) 1996-10-17
WO1996032415A1 (fr) 1996-10-17
CZ317697A3 (cs) 1998-03-18
CZ291646B6 (cs) 2003-04-16
EP0835265A1 (fr) 1998-04-15
NO974537L (no) 1997-10-01

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